Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heparin is widely used as the anticoagulant of choice for cardiopulmonary bypass. However, some patients exposed to heparin therapies develop heparin-induced thrombocytopenia (HIT). Severe complications of HIT-induced thrombosis may lead to end-organ dysfunction and death. Bivalirudin, a hirudin analog, is an alternative anticoagulant that may be used in the patient with HIT without inducing thrombotic disorders. This case report provides a look at the successful use of bivalirudin as the sole anticoagulant in a patient diagnosed with HIT undergoing minimally invasive cardiothoracic surgery requiring cardiopulmonary bypass for severe mitral insufficiency. An 80-year-old male presented to the operating room for a minimally invasive mitral valve repair. Past medical history included mitral valve prolapse, atrial fibrillation, hypertension, and congestive heart failure. Preoperative evaluation noted the existence of HIT with heparin exposure 2 months prior. The decision was made to use bivalirudin as the sole anticoagulant for the operative procedure. Anticoagulation evaluation was performed with both high-does thrombin time (HiTT) and Celite activated clotting time tubes for comparison using a Hemochron device. Cardiopulmonary bypass was initiated, and the patient's mitral valve was repaired using a 34-mm annuloplasty ring. The patient was successfully weaned from bypass. No complications or evidence of HIT exacerbation were noted in the postoperative course.
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PMID:Anticoagulant monitoring techniques in a heparin-induced thrombocytopenia patient undergoing cardiopulmonary bypass using bivalirudin anticoagulant. 1567 82

Unfractionated heparin is associated with a high rate of bleeding and thrombotic complications during peripheral vascular interventions (PVIs). Newer anticoagulants such as direct thrombin inhibitors might offer significant advantages over heparin. Early data with bivalirudin in the peripheral circulation are promising. Bivalirudin appears safe and effective when used during PVIs. Data with the use of other direct thrombin inhibitors (hirudin, r-hirudin, argatroban, and melagatran) in peripheral interventions are still lacking. Among these, argatroban and melagatran have pharmacologic properties that might offer some advantages in PVI, but further studies are needed to demonstrate their safety and effectiveness.
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PMID:Complications in peripheral vascular interventions: emerging role of direct thrombin inhibitors. 1571 17

Direct thrombin inhibitors (DTIs) are a new class of therapeutics possessing theoretic advantages over unfractionated heparin (UFH). In contrast to UFH, DTIs do not activate platelets, have no circulating inhibitors, and bind to both free and clot-bound thrombin. These theoretical advantages have spurred clinical trials investigating DTIs in a variety of cardiovascular indications. Currently, the major role for DTIs in cardiology is as an adjunct during percutaneous coronary intervention (PCI). Such a role stems from the results of the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 randomized trial, in which bivalirudin with provisional abciximab was demonstrated to be equivalent to UFH plus planned abciximab with respect to ischemic endpoints, while being associated with less bleeding. Ongoing clinical trials will define the role of bivalirudin as an adjunct to primary PCI for ST-segment elevation myocardial infarction and in non-ST segment elevation acute coronary syndrome as an adjunct to an early invasive strategy.
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PMID:Direct thrombin inhibitors. 1598 22

Bivalirudin (Angiomax) is a thrombin-inhibiting oligopeptide that was developed via rational drug design as a hirudin analogue ('hirulog'). Similar to hirudin, it is a bivalent thrombin inhibitor, as its 20-amino acid structure combines a carboxy-terminal region that recognises thrombin's fibrin(ogen)-binding site, and an amino-terminal tetrapeptide that inhibits the active site of thrombin, connected by a tetraglycine spacer. It has certain pharmacological advantages over hirudin, including enzymic metabolism (less dependence on renal clearance) and low immunogenicity (reduced potential for anaphylaxis). Bivalirudin is approved for use in percutaneous transluminal coronary angioplasty (PTCA), and is undergoing active investigation for anticoagulation during cardiac surgery, both 'off-pump' and with cardiopulmonary bypass ('on-pump'). Anecdotal 'off-label' experience for the treatment of heparin-induced thrombocytopenia shows promise.
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PMID:Bivalirudin: a review. 1601 85

Bivalirudin (Angiox, Angiomax) is a synthetic 20-amino acid peptide analogue of hirudin. It is a direct thrombin inhibitor that binds specifically and reversibly to both fibrin-bound and unbound thrombin. Intravenous bivalirudin is approved in Europe for use as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI). In the US, bivalirudin is approved in patients with unstable angina pectoris undergoing percutaneous transluminal coronary angioplasty (PTCA) and has recently been approved for use with provisional glycoprotein (GP) IIb/IIIa inhibition in patients undergoing PCI. Bivalirudin plus provisional GP IIb/IIIa inhibition is effective in patients undergoing PCI. The large, well controlled REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events) study showed that bivalirudin plus provisional GP IIb/IIIa inhibition was noninferior to heparin plus planned GP IIb/IIIa inhibition and that bivalirudin was associated with a reduced risk of bleeding complications. In patients with heparin-induced thrombocytopenia (HIT), bivalirudin was effective against ischaemic events and there was a low incidence of bleeding complications. Bivalirudin should be considered as an alternative to heparin plus planned GP IIb/IIIa inhibition in any patient undergoing urgent or elective PCI, especially in any patient with a high risk of bleeding complications.
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PMID:Bivalirudin: a review of its use in patients undergoing percutaneous coronary intervention. 1611 83

Thromboembolism is a common cause of death and disability. Heparin or warfarin, the current standard management for thromboembolism may cause serious bleeding complications. Thrombin is the key enzyme of coagulation. Hirudin, the most potent natural thrombin-specific inhibitor, was first isolated from leech salivary fluid. Synthetic thrombin-specific inhibitors are rationally designed based on the knowledge on the structures of the activate site of thrombin. Thrombin-specific inhibitors are the current best choice for the treatment of heparin-induced thrombocytopenia (HIT). Recombinant hirudins (such as desirudin) were also approved for the prevention of thrombosis after hip or knee surgery. Bivalirudin (hirulog-1 or Angiomax), in adjunct to aspirin, was approved for prevention of thrombosis in patients with unstable angina following angioplasty. Argatroban has been used for the treatment of HIT, peripheral and cerebral thrombotic diseases. The benefit of using thrombin-specific inhibitors alone in acute myocardial infarction or unstable angina remains uncertain. Some of thrombin-specific inhibitors which are small molecules are orally active. The major concern for the use of thrombin-specific inhibitors is bleeding complication. The efficacy, safety, stability and oral bioavailability may be considerably improved through structural optimization. A growing line of evidence suggests that statins, the most commonly prescribed cholesterol lowering drug, may inhibit thrombin generation. Statins do not cause bleeding and have an outstanding safety profile. The findings suggest that further development of thrombin-specific inhibitors and exploration of the potential applications of non-specific thrombin inhibitors, including statins, may improve the prevention and management of thromboembotic events.
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PMID:Inhibition of thrombin: relevance to anti-thrombosis strategy. 1614 17

Unfractionated heparin, derived from porcine intestine, is the prototype of a rapidly acting anticoagulant. It has been used for over 60 years to arrest or prevent thrombus growth. Low-molecular-weight heparins, available in the last 20 years, are manufactured from unfractionated heparin and have superior dose-response relationships because of fewer nonspecific reactions with plasma proteins and cells. Fondaparinux is a recently approved five-saccharide synthetic molecule that carries the evolution of heparin further. It is a pure Xa inhibitor, with minimal nonspecific interactions. It does not appear to elicit the antibody that leads to heparin-induced thrombocytopenia (HIT). All of these agents are given either intravenously or subcutaneously. They act indirectly by activating the natural plasma inhibitor, antithrombin III. Direct thrombin inhibitors bind directly to thrombin's active site without interaction with the cofactor, antithrombin III. Lepirudin (Refludan; Berlex, Wayne, NJ) and argatroban (Argatroban; GlaxoSmithKline, Research Triangle Park, NC) are given intravenously and are usually used in HIT and thrombosis associated with HIT. Bivalirudin (Angiomax; The Medicines Company, Parsippany, NJ) is a parenteral direct thrombin used in place of heparin in percutaneous coronary interventions. Ximelagatran (Exanta; AstraZeneca, Wilmington, DE) is an oral direct thrombin inhibitor under development for both acute and chronic anticoagulation.
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PMID:Heparin and other rapidly acting anticoagulants. 1616 87

The occurrence of intracoronary thrombus during percutaneous coronary intervention (PCI) is a well-known complication. It has been estimated that it complicates approximately 6% of all coronary procedures. Patients at highest risk for this complication include those with acute ischemic syndromes or with angiographically apparent thrombus. Since the development of PCI, intravenous unfractionated heparin (UFH) has remained the primary antithrombotic therapy for the prevention of periprocedural ischemic complications. The availability of a rapid "point of care'' test for dose individualization (the activated clotting time [ACT]) has facilitated this process. Other forms of antithrombotic therapies such as direct thrombin inhibitors or low-molecular-weight heparin have been proposed as more effective anticoagulants during PCI. Bivalirudin is a direct thrombin inhibitor proven to decrease post-PCI ischemic complication rate compared with UFH and have a lower vascular complication rate compared with glycoprotein IIb/IIIa receptor antagonists. We herein report a case of acute macrothrombus formation during PCI despite adequate ACT achieved with bivalirudin.
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PMID:Intracoronary macrothrombus formation during percutaneous coronary intervention despite optimal activated clotting time using bivalirudin--a case report. 1632 53

The recognition and management of heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia with thrombosis syndrome (HITTS) has been evolving over the past several years. Although HIT is a relatively uncommon adverse event in patients receiving heparin therapy, it bears a significant risk of thrombotic events. If patients are left untreated, 50% can develop thrombosis. Several direct thrombin inhibitors have been studied as alternative anticoagulants in patients with HIT. Lepirudin and argatroban are both approved by the United States Food and Drug Administration (FDA) for the management of HIT. Lepirudin requires dosage adjustments in patients with renal insufficiency and has potential for antibody formation. Argatroban requires dosage adjustments in patients with hepatic insufficiency. Argatroban increases the international normalized ratio when coadministered with warfarin, leading to dosage difficulties when transitioning to warfarin therapy. Bivalirudin is the most recent direct thrombin inhibitor to be introduced to the market, but it is not currently FDA approved for HIT. Controversy still exists over which direct thrombin inhibitor to use, especially in acutely ill patients and in those requiring invasive or surgical procedures. Bivalirudin has a relatively short half-life and a predictable response, which makes it attractive as an anticoagulant in patients requiring invasive or surgical procedures, those who are acutely ill, or patients with both renal and hepatic insufficiency. It offers promise as an additional direct thrombin inhibitor for use in patients with HIT, but additional studies need to be performed to further define its use.
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PMID:Treatment of heparin-induced thrombocytopenia: is there a role for bivalirudin? 1646 27

Bivalirudin (Hirulog, Angiomax) is a specific, reversible and direct thrombin inhibitor with a predictable anticoagulant effect. It is cleared by both proteolytic cleavage and renal mechanisms, predominantly glomerular filtration. Bivalirudin inhibits both circulating thrombin and fibrin bound thrombin directly by binding to thrombin catalytic site and anion-binding exosite I in a concentration-dependent manner. Bivalirudin prolongs activated partial thromboplastin time, prothrombin time, thrombin time and activated clotting time (ACT). ACT levels with bivalirudin do not correlate with its clinical efficacy. Bivalirudin with a provisional GpIIb/IIIa inhibitor is indicated in elective contemporary percutaneous coronary intervention (PCI). In respect to combined ischemic and hemorrhagic endpoints of death, myocardial infarction, unplanned urgent revascularization and major bleeding during PCI (including subgroups of patients with renal impairment and diabetes) bivalirudin is not inferior to unfractioned heparin and planned GpIIb/IIIa inhibitors. In addition, bivalirudin has been consistently shown to have significantly less in-hospital major bleeding than heparin alone or heparin in combination with a GpIIb/IIIa inhibitor. Bivalirudin appears to be also safe and effective during PCI in patients with heparin-induced thrombocytopenia. Finally, data from PCI studies support the safety and efficacy of bivalirudin, although its direct randomized comparison with unfractionated heparin is lacking.
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PMID:Bivalirudin: pharmacology and clinical applications. 1661 33


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